Administration Of Levosimendan Research Articles

Impact of Anesthetics on Cardioprotection Induced by Pharmacological Preconditioning.

Anesthetics, especially propofol, are discussed to influence ischemic preconditioning. We investigated whether cardioprotection by milrinone or levosimendan is influenced by the clinically used anesthetics propofol, sevoflurane or dexmedetomidine. Hearts of male Wistar rats were randomised, placed on a Langendorff system and perfused with Krebs–Henseleit buffer (KHB) at a constant pressure of 80 mmHg. All hearts underwent 33 min of global ischemia and 60 min of reperfusion. Three different anesthetic regimens were conducted throughout the experiments: propofol (11 μM), sevoflurane (2.5 Vol%) and dexmedetomidine (1.5 nM). Under each anesthetic regimen, pharmacological preconditioning was induced by administration of milrinone (1 μM) or levosimendan (0.3 μM) 10 min before ischemia. Infarct size was determined by TTC staining. Infarct sizes in control groups were comparable (KHB-Con: 53 ± 9%, Prop-Con: 56 ± 9%, Sevo-Con: 56 ± 8%, Dex-Con: 53 ± 9%; ns). Propofol completely abolished preconditioning by milrinone and levosimendan (Prop-Mil: 52 ± 8%, Prop-Lev: 52 ± 8%; ns versus Prop-Con), while sevoflurane did not (Sevo-Mil: 31 ± 9%, Sevo-Lev: 33 ± 7%; p < 0.05 versus Sevo-Con). Under dexmedetomidine, results were inconsistent; levosimendan induced infarct size reduction (Dex-Lev: 36 ± 6%; p < 0.05 versus Dex-Con) but not milrinone (Dex-Mil: 51 ± 8%; ns versus Dex-Con). The choice of the anesthetic regimen has an impact on infarct size reduction by pharmacological preconditioning.

Levosimendan for patients with heart failure undergoing major oncological surgery: A randomised blinded pilot study.

Background and Aims:Cardiovascular diseases and cancer are among the leading causes of mortality worldwide. The aim of this study is to evaluate the efficacy and safety of preoperative administration of levosimendan in patients with chronic heart failure (CHF) scheduled for major abdominal oncologic surgery.Methods:This study included 60 patients with abdominal malignancy, ejection fraction (EF) <35% and CHF scheduled for surgery under isoflurane-fentanyl anaesthesia and were managed in the surgical intensive care unit perioperatively. They were randomised to receive levosimendan infusion (n = 30) at a dose of 0.1 μg/kg/min or placebo (n = 30) for 24 hours before surgery.Results:The risk of hypotension (RR: 0.40, 95% CI: 0.19-0.83) or decompensated heart failure (RR: 0.31, 95% CI: 0.12-0.76) was significantly lower in the levosimendan group. The ejection fraction, cardiac index and stroke volume index were significantly higher in the levosimendan group after surgery (P < 0.001). Duration of postoperative ventilation and hospital stay were significantly shorter in the levosimendan group (P < 0.001) while the frequency of dysrhythmia, deterioration of renal function and sepsis was comparable.Conclusion:In patients with low EF <35% and CHF, administration of levosimendan for 24 hours before major abdominal oncologic surgeries may reduce the risk of hypotension and decompensated heart failure and may improve cardiac function.

Efficacy of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery: a Meta-analysis

Objective To explore the effect of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. Methods Databases including PubMed, EMBASE and Cochrane database were systematically queried to identify randomized controlled trial (RCT) research regarding levosimendan treatment for patients with left ventricular dysfunction undergoing cardiac surgery published from inception to July 2017. Meta-analysis was performed using RevMan 5.3. Relevant outcomes included early mortality, acute kidney injury, need for renal replacement therapy, hypotension and arrhythmia. Results Nine literatures with a total of 1 464 participants were included, with 736 patients in levosimendan group and 728 patients in control group respectively. Compared with control drugs, levosimendan reduced early mortality [odds ratio (OR)=0.5, 95% confidence interval (CI): 0.31-0.81, P=0.004], the incidence of acute kidney injury (OR=0.5, 95%CI: 0.32-0.78, P=0.003) and renal replacement therapy (OR=0.54, 95%CI: 0.32-0.90, P=0.03) in patients undergoing cardiac surgery, but did not affect the incidence of hypotension and arrhythmias (OR=1.29, 95%CI: 0.83-1.99, P=0.26. OR=0.65, 95%CI: 0.32-1.35, P=0.25). Conclusions Perioperative administration of levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery may improve patient′s prognosis and reduce complications. The scope of this study is small, so more high quality RCT research are needed to provide more conclusive evidence regarding the benefit of this drug. Key words: Levosimendan; Cardiac insufficiency; Cardiac surgery; Mortality; Acute kidney injury

Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period.

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first‐in‐class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double‐blind, placebo‐controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time‐averaged proportional change in N‐terminal pro‐brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.

Levosimendan for Perioperative Cardioprotection: Myth or Reality?

Background: Levosimendan is a calcium sensitizer drug causing increased contractility in the myocardium and vasodilation in the vascular system. It is mainly used for the therapy of acute decompensated heart failure. Several studies on animals and humans provided evidence of the cardioprotective properties of levosimendan including preconditioning and anti-apoptotic. In view of these favorable effects, levosimendan has been tested in patients undergoing cardiac surgery for the prevention or treatment of low cardiac output syndrome. However, initial positive results from small studies have not been confirmed in three recent large trials.Aim: To summarize levosimendan mechanisms of action and clinical use and to review available evidence on its perioperative use in a cardiac surgery setting.Methods: We searched two electronic medical databases for randomized controlled trials studying levosimendan in cardiac surgery patients, ranging from January 2000 to August 2017. Meta-analyses, consensus documents and retrospective studies were also reviewed.Results: In the selected interval of time, 54 studies on the use of levosimendan in heart surgery have been performed. Early small size studies and meta-analyses have suggested that perioperative levosimendan infusion could diminish mortality and other adverse outcomes (i.e. intensive care unit stay and need for inotropic support). Instead, three recent large randomized controlled trials (LEVO-CTS, CHEETAH and LICORN) showed no significant survival benefits from levosimendan. However, in LEVO-CTS trial, prophylactic levosimendan administration significantly reduced the incidence of low cardiac output syndrome.Conclusions: Based on most recent randomized controlled trials, levosimendan, although effective for the treatment of acute heart failure, can't be recommended as standard therapy for the management of heart surgery patients. Further studies are needed to clarify whether selected subgroups of heart surgery patients may benefit from perioperative levosimendan infusion.

Assessment of the Effects of Levosimendan and Nigella Sativa on Myocardial Ischemia Reperfusion Injury in Rats

Objective: Ischemia-reperfusion injury is a chain of events put in place by tissue ischemia. Reperfusion following the damage of cell causes an active inflammatory response. In our research we tried to evaluate the protective effect of Levosimendan and Nigella Sativa on myocardial ischemia-reperfusion injury in rats. Methods: We included twenty-four Wistar albino rats in our research. The rats were randomly divided into four experimental groups. The coronary arteries of rats in Group C (control group) were not occluded or reperfused. Left anterior descending coronary artery was ligated for 30 min to perform myocardial IR and then reperfused for 2 h in the IR (IR), IR-Levosimendan (24µg/kg) (IRL) and IR-Nigella Sativa (0.2 mL/kg) (IRNS) group. Results: Inflammation findings were significantly higher in the IR group compared with the C, IR-NS, and IR-L groups (p=0.001, p=0.019, p=0.019, respectively). Compared with the C, IR-NS, and IR-L groups, the microscopic myocardial disorganization was significantly higher among the IR group (p<0.0001, p=0.007, p=0.001, respectively). The light microscopic myocardial tissue interstitial fibrosis levels were significantly higher in the IR group than in the C, IR-NS, and IR-L groups (p<0.0001, p=0.044, p=0.003, respectively). Conclusion: Levosimendan and NS administration at the beginning of myocardial ischemia can provide varying degrees of protection against negative effects of variations in light microscopic inflammation findings, myocardial disorganization degrees and myocardial tissue interstitial fibrosis levels.

Cardiogenic shock complicating peripartum cardiomyopathy: Importance of early left ventricular unloading and bromocriptine therapy.

Acute peripartum cardiomyopathy complicated by cardiogenic shock is a rare but life-threatening disease. A prolactin fragment is considered causal for the pathogenesis of peripartum cardiomyopathy. This analysis sought to investigate the role of early percutaneous mechanical circulatory support with micro-axial flow-pumps and/or veno-arterial extracorporeal membrane oxygenation in combination with the prolactin inhibitor bromocriptine in refractory cardiogenic shock complicating peripartum cardiomyopathy. In this single-centre analysis, five peripartum cardiomyopathy patients with refractory cardiogenic shock received mechanical circulatory support with either Impella CP microaxial pump only (n=2) or in combination with veno-arterial extracorporeal membrane oxygenation (n=3) in the setting of biventricular failure. All patients were mechanically ventilated. In all cases mechanical circulatory support was combined with bromocriptine therapy and early administration of levosimendan. All patients survived the acute phase of refractory cardiogenic shock. Mechanical circulatory support using a micro-axial pump allowed to significantly reduce catecholamine dosage. Remarkably, early left ventricular support with micro-axial flow-pumps resulted in myocardial recovery whereas delayed Impella (mechanical circulatory support) implantation was associated with poor left ventricular recovery. Mechanical circulatory support in patients with refractory cardiogenic shock complicating peripartum cardiomyopathy was associated with a 30-day survival of 100% and a favourable outcome. Notably, early left ventricular unloading combined with bromocriptine therapy was associated with left ventricular recovery. Therefore, an immediate transfer to a tertiary hospital experienced in mechanical circulatory support in combination with bromocriptine treatment seems indispensable for successful treatment of peripartum cardiomyopathy complicated by cardiogenic shock.

Calcium Sensitizers in Cardiac Surgery: Who, When, How and Why?

Inodilators are a heterogeneous group of drugs with vasodilatory and inotropic effects. The cardioprotective effect of levosimendan is multifactorial, but now research on levosimendan is focused on the organ-protective properties of this drug in different settings, the regimen that seems to provide the greatest cardiologic and systemic benefits is early administration of levosimendan. We try to answer four questions in this review, which type of patients need this drug? what is the best time to start with it? and the best way that we could give it and finally the reasons for use it.

Assessment of the effects of levosimendan and thymoquinone on lung injury after myocardial ischemia reperfusion in rats.

AimThe aim of this study was to investigate the effects of levosimendan and thymoquinone (TQ) on lung injury after myocardial ischemia/reperfusion (I/R).Materials and methodsTwenty-four Wistar albino rats were included in the study. The animals were randomly assigned to 1 of 4 experimental groups. In Group C (control group), left anterior descending artery was not occluded or reperfused. Myocardial I/R was induced by ligation of the left anterior descending artery for 30 min, followed by 2 h of reperfusion in the I/R, I/R-levosimendan (24 µg/kg) (IRL) group, and I/R-thymoquinone (0.2 mL/kg) (IRTQ) group. Tissue samples taken from the lungs of rats were histochemically stained with H&E and immunohistochemically stained with p53, Bcl 2, Bax, and caspase 3 primer antibodies.ResultsIncreased expression of p53 and Bax was observed (4+), especially in the I/R group. In IRTQ and IRL groups, expression was also observed at various locations (2+, 3+). H&E staining revealed that that the lungs were severely damaged and the walls of the alveoli were too thick, the number of areas examined was increased during the evaluation. Caspase 3 expression was observed to be at an (1+, 2+) intensity that was usually weak and diffuse in multiple areas. Bcl 2 was not found to be expressed in any of the tissues. H&E staining revealed that that the lungs were severely damaged in the I/R group, with the walls of the channels and alveoli thickened and edematous, and also an intense inflammatory cell migration was observed. Immunohistochemical staining was more prominent in inflammatory areas and structures around the terminal bronchioles.ConclusionThe findings in our study have shown that administration of levosimendan and TQ during I/R increases expression of caspase 3, p53, and Bax in lung tissue and has a protective effect on lung as distant organ. We suggest that findings of this study be elucidated with further large-scale clinical studies.

Effect of Levosimendan on Renal Outcome in Cardiac Surgery Patients With Chronic Kidney Disease and Perioperative Cardiovascular Dysfunction: A Substudy of a Multicenter Randomized Trial

Acute kidney injury (AKI) occurs frequently after cardiac surgery. Levosimendan might reduce the incidence of AKI in patients undergoing cardiac surgery. The authors investigated whether levosimendan administration could reduce AKI incidence in a high-risk cardiac surgical population. Post hoc analysis of a multicenter randomized trial. Cardiac surgery operating rooms and intensive care units of 14 centers in 3 countries. The study comprised 90 patients who underwent mitral valve surgery with an estimated glomerular filtration rate <60 mL/min/1.73 m2 and perioperative myocardial dysfunction. Patients were assigned randomly to receive levosimendan (0.025-0.2 μg/kg/min) or placebo in addition to standard inotropic treatment. Forty-six patients were assigned to receive levosimendan and 44 to receive placebo. Postoperative AKI occurred in 14 (30%) patients in the levosimendan group versus 23 (52%) in the placebo group (absolute difference -21.8; 95% confidence interval -41.7 to -1.97; p = 0.035). The incidence of major complications also was lower (18 [39%]) in the levosimendan group versus that in the placebo group (29 [66%]) (absolute difference -26.8 [-46.7 to -6.90]; p = 0.011). A trend toward lower serum creatinine at intensive care unit discharge was observed in the levosimendan group (1.18 [0.99-1.49] mg/dL) versus that in the placebo group (1.39 [1.05-1.76] mg/dL) (95% confidence interval -0.23 [-0.49 to 0.01]; p = 0.07). Levosimendan may improve renal outcome in cardiac surgery patients with chronic kidney disease undergoing mitral valve surgery who develop perioperative myocardial dysfunction. Results of this exploratory analysis should be investigated in future properly designed randomized controlled trials.

Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: the LION-HEART multicentre randomised trial.

The LION-HEART study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial evaluating the efficacy and safety of intravenous administration of intermittent doses of levosimendan in outpatients with advanced chronic heart failure. Sixty-nine patients from 12 centres were randomly assigned at a 2:1 ratio to levosimendan or placebo groups, receiving treatment by a 6-hour intravenous infusion (0.2 μg/kg/min without bolus) every 2 weeks for 12 weeks. The primary endpoint was the effect on serum concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) throughout the treatment period in comparison with placebo. Secondary endpoints included evaluation of safety, clinical events and health-related quality of life (HRQoL). The area under the curve (AUC, pg.day/mL) of the levels of NT-proBNP over time for patients who received levosimendan was significantly lower than for the placebo group (344 × 103 [95% Confidence Interval (CI) 283 × 103 -404 × 103 ] vs. 535 × 103 [443 × 103 -626 × 103 ], p = 0.003). In comparison with the placebo group, the patients on levosimendan experienced a reduction in the rate of heart failure hospitalisation (hazard ratio 0.25; 95% CI 0.11-0.56; P = 0.001). Patients on levosimendan were less likely to experience a clinically significant decline in HRQoL over time (P = 0.022). Adverse event rates were similar in the two treatment groups. In this small pilot study, intermittent administration of levosimendan to ambulatory patients with advanced systolic heart failure reduced plasma concentrations of NT-proBNP, worsening of HRQoL and hospitalisation for heart failure. The efficacy and safety of this intervention should be confirmed in larger trials.

Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

It is currently unknown whether levosimendan can improve clinical outcomes in patients undergoing cardiac surgery. This meta-analysis aimed to assess the effect of levosimendan on mortality and the duration of intensive care unit (ICU) and hospital stay in adult patients undergoing cardiac surgery. A comprehensive search for eligible articles was conducted in PubMed, OVID and Cochrane databases of clinical trials and the Web of Science from database inception to August 2017. Stata/SE 11.0 was used to calculate the pooled odds ratio for postoperative mortality and the pooled standardized mean difference (SMD) for the duration of ICU stay and hospital stay. A total of 30 randomized controlled trials were included in the final analysis; the pooled results indicated that perioperative administration of levosimendan was associated with a reduction in postoperative mortality [5.8% vs 8.5%; odds ratio 0.66, 95% confidence interval 0.50-0.86, P = 0.002; I2 = 17.1%; 25 trials; 3239 patients] and length of ICU stay (SMD -0.32, 95% CI -0.58 to 0.06, P = 0.017; I2 = 88.0%; 23 trials; 2536 patients) compared with the control group but not in length of hospital stay (SMD -0.41, 95% CI -0.89 to 0.07, P = 0.094; I2 = 95.9%; 18 trials; 2047 patients). A subanalysis was conducted for trials published after 2015, and it suggested that levosimendan could not reduce the postoperative mortality (odds ratio = 0.91, 95% CI 0.63-1.31, P = 0.626; I2 = 0.9%), length of ICU stay (SMD -0.03, 95% CI -0.32 to 0.27, P = 0.850; I2 = 81.2%) or length of hospital stay (SMD 0.06, 95%CI -0.43 to 0.54, P = 0.821; I2 = 91.3%). To summarize, the evidence from studies published in the last 3 years indicated that perioperative administration of levosimendan was not associated with better clinical outcomes in adult patients undergoing cardiac surgery.

Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: a meta-analysis of randomized trials.

AimsIntermittent levosimendan administration has been suggested to improve survival in patients with advanced heart failure (AdHF). Quality of life is a key issue for AdHF patients and is negatively affected by frequent hospitalizations.Methods and resultsCENTRAL, Google Scholar, MEDLINE/PubMed, Scopus, and the Cochrane Central Register of clinical trials (updated 15/1/2017) were searched for randomized controlled trials investigating the effect of intermittent levosimendan administration in patients with AdHF. The primary outcome was the number of patients requiring rehospitalization 3 months after the end of treatment. A total of 319 patients from six trials were included. Overall pooled analysis showed that the use of levosimendan was associated with a significant reduction in the number of rehospitalizations at 3 months: 33/207 (16%) vs. 39/113 (35%), risk ratio 0.40, 95% confidence interval 0.27–0.59, P < 0.001, I 2 = 0%. This result was confirmed by sensitivity analyses.ConclusionsWithin the limitations of this meta‐analysis including also studies in which endpoints were not independently adjudicated and not clearly specified, repetitive or intermittent administration of levosimendan for patients with AdHF was associated with a reduction in the rehospitalization rate at 3 months. Large, high‐quality randomized controlled trials are needed to confirm this finding.

Levosimendan mitigates coagulopathy and organ dysfunction in rats with endotoxemia

BackgroundIn patients with severe sepsis, pro-inflammatory cytokines and subsequent activation of tissue factors trigger a cascade of events that lead to coagulation dysfunction and multiple organ failure. It has been shown that levosimendan has protective effects against tissue injury caused by endotoxin. The purpose of this study was to evaluate the effects of levosimendan on consumptive coagulopathy and organ dysfunction in an endotoxemic animal model induced by lipopolysaccharide (LPS). MethodsForty-six male adult Wistar rats were randomly divided into four groups: 1) control group (n = 10), an intravenous infusion of 5% dextrose 1.2 mL/kg for 20 min and 0.03 mL/kg/min for 4 h; 2) the levosimendan-treated control group (n = 12), an intravenous levosimendan infusion (24 μg/kg for 20 min plus 0.6 μg/kg/min for 4 h); 3) the LPS group (n = 12), an intravenous LPS (4 mg/kg) infusion followed by dextrose administration; and 4) the levosimendan-treated LPS group (n = 12), an intravenous LPS infusion followed by levosimendan treatment. Various parameters of hemodynamics, biochemistry, hemostasis and inflammatory response were examined during the experimental period. ResultsThe administration of levosimendan significantly attenuated (i) consumptive coagulopathy displayed by thromboelastography, (ii) the decreases of platelet count and plasma fibrinogen level, (iii) injury in the lung, liver and kidney, and (iv) the rise in plasma interleukin-6 in rats treated with LPS. ConclusionThe treatment of LPS rats with levosimendan was found to reduce organ injury and coagulopathy. These protective effects may be attributed to the anti-inflammatory effects of this drug.

Use of vasopressors and inotropics in cardiogenic shock

Vasoactive drugs and inotropic agents are important for the hemodynamic management of cardiogenic shock. In this article the use of different vasoactive and ionotropic drugs in cardiogenic shock is presented. Hemodynamic management during cardiogenic shock occurs after initial moderate volume delivery by dobutamine to increase inotropism. If adequate perfusion pressures are not achieved norepinephrine is administered. If asufficient increase in cardiac performance can still not be achieved by the treatment, administration of levosimendan or phosphodiesterase (PDE) inhibitors may be necessary. Levosimendan is superior to PDE inhibitors for patients in cardiogenic shock. The aim of hemodynamic management in cardiogenic shock is to allow the transient use of inotropics and vasopressors in the lowest necessary dose and only as long as necessary. The daily question is whether the dose can be reduced or in the case of deterioration whether the use of an extracorporeal circulatory support system should be considered. There are currently no available data on mortality that demonstrate the benefit of hemodynamic monitoring using target criteria. The advantage, however, results from the economic use of inotropics and vasopressors by certain target criteria.

Intracoronary administration of levosimendan in patients with acute coronary syndromes and decreased left ventricular ejection fraction undergoing coronary artery bypass graft surgery

In cardiac surgery patients, intracoronary (IC) administration of levosimendan can provide optimal drug spread, enabling ef-fective manifestation of favorable drug effects and avoiding potentially harm-ful systemic hypotension. This could be beneficial in acute coronary syndromes (ACS) with decreased left ventricular ejec-tion fraction (LVEF). We present ten cases of IC administration of levosimendan in ACS manifested as ST segment elevation myocardial infarction, non-ST segment el-evation myocardial infarction or unstable angina pectoris. All patients underwent coronary artery bypass graft (CABG) sur-gery, performed as an “off-pump” or “on-pump”/“off-clamp” procedure (latter one with the use of cardiopulmonary bypass on the beating heart). Levosimendan was ad-ministered as an IC bolus (125-250 μg) in each coronary artery graft (2-3 grafts). In-travenous (IV) levosimendan infusion con-tinued (0.1-0.2 μg•kg-1•min-1) after graft placements (24-48 h), with IV infusion of norepinephrine (0.1 mg•ml-1), if needed. Cardiac function was assessed using LVEF (%) (Teicholz), thermodilution cardiac in-dex (CI) (ml•m-2), and systemic vascular resistance (SVR) (dynes•sec•cm-5). Nonparametric Wilcoxon signed-ranks test [presented as median (MED) with interquartile range (IQR)] indicated a sig-nificant difference between preoperative vs. immediate postoperative CI, SVR, and LVEF in all cases [2.2 (1.9-2.5) vs. 3.1 (2.9-3.4) ml•m-2, 1173.0 (1062.7-1278.2) vs. 882.5 (763.5-993.0) dynes•sec•cm-5, 44.5 (36.0-46.7) vs. 53.5 (45.7-59.2) %, respec-tively] (P=0.005), i.e. IC administration of levosimendan was associated with prompt improvement of intraoperative hemody-namics and cardiac contractility. IC ad-ministration of levosimendan may be a promising alternative method for improv-ing decreased cardiac function in acute cardiac ischemia, besides necessary surgi-cal revascularization.

Levosimendan accelerates recovery in patients with takotsubo cardiomyopathy.

The aim of this study was to determine the efficacy and safety of levosimendan in takotsubo cardiomyopathy (TC). The study was conducted in a retrospective design and 42 consecutive patients were enrolled in 6 cardiovascular centers in Turkey. The records of TC patients having left ventricular ejection fraction (LVEF) £ 35% were examined at admission, discharge and recovery period including their clinical and echocardiographic data. Of these 42 TC patients, 17 were treated with loading dose and i.v. infusion of levosimendan (group 1) and 25 were treated without levosimendan (group 2). Echocardiographic findings at admission and at discharge were similar and no serious complications were observed in either group. However recovery period including the interval of 50% increase in LVEF, time to achieve the baseline troponin values and hospitalization were significantly lower in patients taking levosimendan. This is the first study using loading dose and subsequent continuous intravenous administration of levosimendan demonstrating accelerated recovery in patients with TC.

Impact of prophylactic administration of Levosimendan on short-term and long-term outcome in high-risk patients with severely reduced left-ventricular ejection fraction undergoing cardiac surgery - a retrospective analysis.

BackgroundPatients with severely reduced left-ventricular ejection fraction carry a high risk of morbidity and mortality after cardiac surgery. Levosimendan can be used prophylactically in these patients having shown positive effects on short-term outcome. However, effects on long-term outcome and patient subgroups benefiting the most are unknown. We aim to address these topics with real-life data from our clinical practice.MethodsTwo hundred eigthy eight patients with preoperative LVEF ≤ 35% underwent cardiac surgery with cardiopulmonary bypass between 2009 and 2013. Thereof, 246 were included in the matched analysis. Eigthy two patients received 12.5mg Levosimendan starting at induction of anesthesia. Outcomes of patients undergoing coronary artery bypass grafting surgery (n = 103), isolated valve surgery/ascending aortic surgery (n = 45) and those undergoing combination procedures (n = 98) were analyzed separately. Additionally, multivariate regression analysis was conducted in order to identify predictors of short-term outcome parameters for different subgroups of patients.ResultsThirty days mortality rates of 16% in the Levosimendan group and 21% in the control group (OR 0.7; 95%–CI 0.36–1.5; p = 0.37) were observed. Levosimendan showed a positive effect on postoperative renal function. A higher rate of new-onset atrial fibrillation (OR 4.0; 95%–CI 2.2–7-2; p < 0.0001) was observed in the Levosimendan group. Follow-up until three years postoperatively showed no differences in long-term survival between the groups.ConclusionProphylactic administration of Levosimendan did not affect overall short- and long-term outcomes. The value of prophylactic use of Levosimendan remains questionable and more data is needed to confirm subgroups that might benefit most.Electronic supplementary materialThe online version of this article (doi:10.1186/s13019-016-0556-2) contains supplementary material, which is available to authorized users.

Levosimendan Administration in Limb Ischemia: Multicomponent Signaling Serving Kidney Protection.

Aims and ObjectivesAcute renal failure is a severe complication of lower extremity major arterial reconstructions, which could even be fatal. Levosimendan is a dual-acting positive inotropic and vasodilatory agent, which is suspected to have protective effects against cardiac ischemia. However, there is no data available on lower limb or remote organ ischemic injuries therefore the aim of the study was to investigate the effect of levosimendan on lower limb ischemia-reperfusion injury and the corollary renal dysfunction.MethodsMale Wistar rats underwent 180 min bilateral lower limb ischemia followed by 4 or 24 hours of reperfusion. Intravenous Levosimendan was administered continuously (0.2μg/bwkg/min) throughout the whole course of ischemia and the first 3h of reperfusion. Results were compared with sham-operated and ischemia-reperfusion groups. Hemodynamic monitoring was performed by invasive arterial blood pressure measurement. Kidney and lower limb muscle microcirculation was registered by a laser Doppler flowmeter. After 4h and 24h of reperfusion, serum, urine and histological samples were collected.ResultsSystemic hemodynamic parameters and microcirculation of kidney and the lower limb significantly improved in the Levosimendan treated group. Muscle viability was significantly preserved 4 and 24 hours after reperfusion. At the same time, renal functional laboratory tests and kidney histology demonstrated significantly less expressive kidney injury in Levosimendan groups. TNF-α levels were significantly less elevated in the Levosimendan group 4 hours after reperfusion.ConclusionThe results claim a protective role for Levosimendan administration during major vascular surgeries to prevent renal complications.

Cardiac support and replacement therapies

Circulatory support represents an integral part within the treatment of the critically ill patient. Sophisticated pharmacologic regimens help to maintain systemic perfusion pressure by increasing vascular tone as well as mediating positive inotropic effects. Besides the administration of catecholamines and phosphodiesterase-III-inhibitors, in particular the administration of levosimendan represents a promising alternative during low-cardiac-output. Nevertheless, sufficient evidence demonstrating a survival benefit for any pharmacologic regimen is nonexistent. In case pharmacological measures do not suffice mechanical cardiopulmonary support (MCS) may be used. MCS may be used during cardiopulmonary resuscitation or a "low-cardiac-output-syndrome" as bridging towards decision, recovery or long-term support. Venoarterial extracorporeal membrane oxygenation (vaECMO) may take over cardiopulmonary function and may improve survival as well as neurological outcome after cardiogenic shock or cardiopulmonary resuscitation.